# 616963

HYPERCALCEMIA, INFANTILE, 2; HCINF2


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
5q35.3 Hypercalcemia, infantile, 2 616963 AR 3 SLC34A1 182309
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal recessive
GROWTH
Other
- Failure to thrive
GENITOURINARY
Kidneys
- Polyuria
- Hypercalciuria
- Nephrocalcinosis
- Reduced tubular phosphate resorption
MUSCLE, SOFT TISSUES
- Muscular hypotonia (in some patients)
METABOLIC FEATURES
- Hypercalcemia
- Hypophosphatemia
- Elevated calcitriol (active 1,25-(OH)2D3) levels (in some patients)
ENDOCRINE FEATURES
- Low parathyroid hormone (PTH) levels
MISCELLANEOUS
- All patients received vitamin D prophylaxis in infancy
MOLECULAR BASIS
- Caused by mutation in the solute carrier family 34 (type II sodium/phosphate cotransporter) member-1 gene (SLC34A1, 182309.0004)
Hypercalcemia, infantile - PS143880 - 2 Entries
Location Phenotype Inheritance Phenotype
mapping key
Phenotype
MIM number
Gene/Locus Gene/Locus
MIM number
5q35.3 Hypercalcemia, infantile, 2 AR 3 616963 SLC34A1 182309
20q13.2 Hypercalcemia, infantile, 1 AR 3 143880 CYP24A1 126065

TEXT

A number sign (#) is used with this entry because of evidence that infantile hypercalcemia-2 (HCINF2) is caused by homozygous or compound heterozygous mutation in the SLC34A1 gene (182309) on chromosome 5q35.


Description

Infantile hypercalcemia is characterized by severe hypercalcemia with failure to thrive, vomiting, dehydration, and nephrocalcinosis (summary by Schlingmann et al., 2016).

For a general phenotypic description and a discussion of genetic heterogeneity of infantile hypercalcemia, see HCINF1 (143880).


Clinical Features

Lameris et al. (2010) reported a female infant who had increased echogenicity of both kidneys on fetal ultrasound. She presented at age 2 months because of failure to thrive, and extensive nephrocalcinosis was noted. Laboratory analysis showed elevated levels of both total and ionized serum Ca(2+), with a 4-fold increase in the calcium/creatinine (Ca/Cr) ratio and low parathyroid hormone (PTH; 168450). Serum calcium levels decreased spontaneously with increase of fluid intake, and her growth resumed at a normal rate. She had recurrent urinary tract infections from age 2 years, and at age 8 she had a slightly decreased creatinine clearance that was attributed to the combination of recurrent urinary tract infections and nephrocalcinosis.

Schlingmann et al. (2016) studied 16 patients from 15 families with infantile hypercalcemia and mutations in the SLC34A1 gene, 1 of whom was the girl reported by Lameris et al. (2010). All patients received vitamin D supplements from birth. Age at onset varied between 20 days and 10 months, with failure to thrive and polyuria being the most frequent clinical symptoms. Renal ultrasound demonstrated medullary nephrocalcinosis in all infants. Retrospective analysis of laboratory data at the time of initial manifestation revealed hypercalcemia and suppressed intact parathyroid hormone (iPTH) levels. During hypercalcemia, active 1,25(OH)2D3 (calcitriol) levels were measured in 11 patients, and were found to be elevated in 6. In a 3.5-year-old Polish girl, whose only symptom had been polyuria, nephrocalcinosis was discovered incidentally at age 18 months; laboratory evaluation showed high-normal serum calcium and iPTH level at the lower normal limit. Reevaluation of phosphate metabolism in these patients revealed hypophosphatemia, and impairment of renal phosphate conservation was demonstrated in 4 of 7 patients for whom data were available.


Clinical Management

Schlingmann et al. (2016) reviewed treatment of 16 patients from 15 families with SLC34A1-associated infantile hypercalcemia (HCINF2). During acute treatment of hypercalcemia, vitamin D supplements were stopped in all patients, and additional therapeutic measures included intravenous rehydration, furosemide, corticosteroids, and ketoconazole, as well as oral phosphate in 6 patients and a low-calcium diet in 4 patients. Serum calcium levels decreased, but tended to be continuously elevated during follow-up in 6 patients. Tubular maximum phosphate resorption (TmP/GFR) was determined during follow-up in 13 patients, with 4 showing low values and 7 having values in the low-normal range. In the majority of patients (11 of 16), iPTH levels normalized during follow-up. In 1 patient in whom SLC34A1 mutations were identified while he was still acutely hypercalcemic and hypophosphatemic, therapeutic measures including oral rehydration and low calcium diet did not correct the hypercalcemia; however, supplementation with oral phosphate resulted in rapid normalization of hypophosphatemia and calcium metabolism, with significant clinical improvement reflected by rapid weight gain. Over the course of treatment, serum FGF23 (605380) went from low-normal to high-normal range. Noting that in SLC34A1-associated infantile hypercalcemia, clinical and laboratory findings persist despite cessation of vitamin D prophylaxis but rapidly respond to phosphate supplementation, Schlingmann et al. (2016) emphasized the importance of early differentiation between HCINF1 and HCINF2.


Pathogenesis

Schlingmann et al. (2016) stated that human and mouse data (see ANIMAL MODEL) together demonstrated that in SLC34A1-associated infantile hypercalcemia, primary renal phosphate wasting caused by defective NaPi-IIa function induces inappropriate production of 1,25(OH)2D3, with subsequent symptomatic hypercalcemia.


Mapping

In 4 patients from 3 families with infantile hypercalcemia who did not have mutations in the CYP24A1 gene (126065), Schlingmann et al. (2016) performed homozygosity mapping and identified an approximately 1.66-Mb interval on chromosome 5q35 with a maximum multipoint lod score of 6.79.


Molecular Genetics

In 4 patients from 3 families with infantile hypercalcemia mapping to chromosome 5q35, Schlingmann et al. (2016) sequenced the candidate gene SLC34A1 and identified homozygous mutations in all 4 patients (182309.0004-182309.0006). Screening of SLC34A1 in 126 additional sporadic patients with infantile hypercalcemia who were negative for mutation in CYP24A1 identified 11 patients with biallelic mutations (see, e.g., 182309.0005, 182309.0007, 182309.0009). In addition, 1 patient with early-onset nephrocalcinosis was homozygous for a 7-bp deletion in the SLC34A1 gene (182309.0009). Most heterozygous carriers were free of renal pathology; however, the parents of 1 proband had kidney stone disease, and the mother of another proband underwent nephrectomy in adolescence after recurrent pyelonephritis and a staghorn calculus.


Animal Model

Schlingmann et al. (2016) studied Slc34a1 knockout mice, and observed that low-phosphate diets resulted in severe hypophosphatemia in knockout mice, whereas wildtype animals remained normophosphatemic. Diets high in vitamin D resulted in vitamin D overload in both knockout and wildtype mice; however, wildtype mice were able to adequately downregulate vitamin D activation. In contrast, knockout mice showed significantly higher levels of CYP27B1 (609506) mRNA and lower levels of CYP24A1 expression than wildtype, resulting in significantly higher levels of 1,25(OH)2D3 and exacerbation of hypercalcemia and hypercalciuria. Schlingmann et al. (2016) suggested that the impaired inhibition of vitamin D activation in hypophosphatemic knockout mice was likely due to suppressed FGF23 levels, which were significantly lower than those of wildtype mice. Even on a low vitamin D diet, the knockout mice showed augmented vitamin D activation. In contrast, high phosphate diets normalized serum phosphate and FGF23 levels, with return of 1,25(OH)2D3 and serum calcium levels to their physiologic ranges.


REFERENCES

  1. Lameris, A. L. L., Huybers, S., Burke, J. R., Monnens, L. A., Bindels, R. J. M., Hoenderop, J. G. J. Involvement of claudin 3 and claudin 4 in idiopathic infantile hypercalcaemia: a novel hypothesis? Nephrol. Dial. Transplant. 25: 3504-3509, 2010. [PubMed: 20466674, related citations] [Full Text]

  2. Schlingmann, K. P., Ruminska, J., Kaufmann, M., Dursun, I., Patti, M., Kranz, B., Pronicka, E., Ciara, E., Akcay, T., Bulus, D., Cornelissen, E. A. M., Gawlik, A., and 16 others. Autosomal-recessive mutations in SLC34A1 encoding sodium-phosphate cotransporter 2A cause idiopathic infantile hypercalcemia. J. Am. Soc. Nephrol. 27: 604-614, 2016. [PubMed: 26047794, images, related citations] [Full Text]


Creation Date:
Marla J. F. O'Neill : 5/26/2016
carol : 01/17/2020
carol : 05/27/2016
alopez : 5/26/2016

# 616963

HYPERCALCEMIA, INFANTILE, 2; HCINF2


ORPHA: 300547;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
5q35.3 Hypercalcemia, infantile, 2 616963 Autosomal recessive 3 SLC34A1 182309

TEXT

A number sign (#) is used with this entry because of evidence that infantile hypercalcemia-2 (HCINF2) is caused by homozygous or compound heterozygous mutation in the SLC34A1 gene (182309) on chromosome 5q35.


Description

Infantile hypercalcemia is characterized by severe hypercalcemia with failure to thrive, vomiting, dehydration, and nephrocalcinosis (summary by Schlingmann et al., 2016).

For a general phenotypic description and a discussion of genetic heterogeneity of infantile hypercalcemia, see HCINF1 (143880).


Clinical Features

Lameris et al. (2010) reported a female infant who had increased echogenicity of both kidneys on fetal ultrasound. She presented at age 2 months because of failure to thrive, and extensive nephrocalcinosis was noted. Laboratory analysis showed elevated levels of both total and ionized serum Ca(2+), with a 4-fold increase in the calcium/creatinine (Ca/Cr) ratio and low parathyroid hormone (PTH; 168450). Serum calcium levels decreased spontaneously with increase of fluid intake, and her growth resumed at a normal rate. She had recurrent urinary tract infections from age 2 years, and at age 8 she had a slightly decreased creatinine clearance that was attributed to the combination of recurrent urinary tract infections and nephrocalcinosis.

Schlingmann et al. (2016) studied 16 patients from 15 families with infantile hypercalcemia and mutations in the SLC34A1 gene, 1 of whom was the girl reported by Lameris et al. (2010). All patients received vitamin D supplements from birth. Age at onset varied between 20 days and 10 months, with failure to thrive and polyuria being the most frequent clinical symptoms. Renal ultrasound demonstrated medullary nephrocalcinosis in all infants. Retrospective analysis of laboratory data at the time of initial manifestation revealed hypercalcemia and suppressed intact parathyroid hormone (iPTH) levels. During hypercalcemia, active 1,25(OH)2D3 (calcitriol) levels were measured in 11 patients, and were found to be elevated in 6. In a 3.5-year-old Polish girl, whose only symptom had been polyuria, nephrocalcinosis was discovered incidentally at age 18 months; laboratory evaluation showed high-normal serum calcium and iPTH level at the lower normal limit. Reevaluation of phosphate metabolism in these patients revealed hypophosphatemia, and impairment of renal phosphate conservation was demonstrated in 4 of 7 patients for whom data were available.


Clinical Management

Schlingmann et al. (2016) reviewed treatment of 16 patients from 15 families with SLC34A1-associated infantile hypercalcemia (HCINF2). During acute treatment of hypercalcemia, vitamin D supplements were stopped in all patients, and additional therapeutic measures included intravenous rehydration, furosemide, corticosteroids, and ketoconazole, as well as oral phosphate in 6 patients and a low-calcium diet in 4 patients. Serum calcium levels decreased, but tended to be continuously elevated during follow-up in 6 patients. Tubular maximum phosphate resorption (TmP/GFR) was determined during follow-up in 13 patients, with 4 showing low values and 7 having values in the low-normal range. In the majority of patients (11 of 16), iPTH levels normalized during follow-up. In 1 patient in whom SLC34A1 mutations were identified while he was still acutely hypercalcemic and hypophosphatemic, therapeutic measures including oral rehydration and low calcium diet did not correct the hypercalcemia; however, supplementation with oral phosphate resulted in rapid normalization of hypophosphatemia and calcium metabolism, with significant clinical improvement reflected by rapid weight gain. Over the course of treatment, serum FGF23 (605380) went from low-normal to high-normal range. Noting that in SLC34A1-associated infantile hypercalcemia, clinical and laboratory findings persist despite cessation of vitamin D prophylaxis but rapidly respond to phosphate supplementation, Schlingmann et al. (2016) emphasized the importance of early differentiation between HCINF1 and HCINF2.


Pathogenesis

Schlingmann et al. (2016) stated that human and mouse data (see ANIMAL MODEL) together demonstrated that in SLC34A1-associated infantile hypercalcemia, primary renal phosphate wasting caused by defective NaPi-IIa function induces inappropriate production of 1,25(OH)2D3, with subsequent symptomatic hypercalcemia.


Mapping

In 4 patients from 3 families with infantile hypercalcemia who did not have mutations in the CYP24A1 gene (126065), Schlingmann et al. (2016) performed homozygosity mapping and identified an approximately 1.66-Mb interval on chromosome 5q35 with a maximum multipoint lod score of 6.79.


Molecular Genetics

In 4 patients from 3 families with infantile hypercalcemia mapping to chromosome 5q35, Schlingmann et al. (2016) sequenced the candidate gene SLC34A1 and identified homozygous mutations in all 4 patients (182309.0004-182309.0006). Screening of SLC34A1 in 126 additional sporadic patients with infantile hypercalcemia who were negative for mutation in CYP24A1 identified 11 patients with biallelic mutations (see, e.g., 182309.0005, 182309.0007, 182309.0009). In addition, 1 patient with early-onset nephrocalcinosis was homozygous for a 7-bp deletion in the SLC34A1 gene (182309.0009). Most heterozygous carriers were free of renal pathology; however, the parents of 1 proband had kidney stone disease, and the mother of another proband underwent nephrectomy in adolescence after recurrent pyelonephritis and a staghorn calculus.


Animal Model

Schlingmann et al. (2016) studied Slc34a1 knockout mice, and observed that low-phosphate diets resulted in severe hypophosphatemia in knockout mice, whereas wildtype animals remained normophosphatemic. Diets high in vitamin D resulted in vitamin D overload in both knockout and wildtype mice; however, wildtype mice were able to adequately downregulate vitamin D activation. In contrast, knockout mice showed significantly higher levels of CYP27B1 (609506) mRNA and lower levels of CYP24A1 expression than wildtype, resulting in significantly higher levels of 1,25(OH)2D3 and exacerbation of hypercalcemia and hypercalciuria. Schlingmann et al. (2016) suggested that the impaired inhibition of vitamin D activation in hypophosphatemic knockout mice was likely due to suppressed FGF23 levels, which were significantly lower than those of wildtype mice. Even on a low vitamin D diet, the knockout mice showed augmented vitamin D activation. In contrast, high phosphate diets normalized serum phosphate and FGF23 levels, with return of 1,25(OH)2D3 and serum calcium levels to their physiologic ranges.


REFERENCES

  1. Lameris, A. L. L., Huybers, S., Burke, J. R., Monnens, L. A., Bindels, R. J. M., Hoenderop, J. G. J. Involvement of claudin 3 and claudin 4 in idiopathic infantile hypercalcaemia: a novel hypothesis? Nephrol. Dial. Transplant. 25: 3504-3509, 2010. [PubMed: 20466674] [Full Text: https://doi.org/10.1093/ndt/gfq221]

  2. Schlingmann, K. P., Ruminska, J., Kaufmann, M., Dursun, I., Patti, M., Kranz, B., Pronicka, E., Ciara, E., Akcay, T., Bulus, D., Cornelissen, E. A. M., Gawlik, A., and 16 others. Autosomal-recessive mutations in SLC34A1 encoding sodium-phosphate cotransporter 2A cause idiopathic infantile hypercalcemia. J. Am. Soc. Nephrol. 27: 604-614, 2016. [PubMed: 26047794] [Full Text: https://doi.org/10.1681/ASN.2014101025]


Creation Date:
Marla J. F. O'Neill : 5/26/2016

Edit History:
carol : 01/17/2020
carol : 05/27/2016
alopez : 5/26/2016